This invention relates to a novel transdermal fertility control system for females and a process for controlling fertility. The system involves transdermal absorption dosage units adapted for adhesion to the female subject designed for fertility control or prevention of an unwanted pregnancy. Further, the invention relates to a method of controlling fertility by utilizing a transdermal system of applying a series of transdermal polymer matrix dosage units having dissolved or microdispersed in the matrix layer effective dosage amounts of an estrogen, preferably ethinyl estradiol and a progestin, preferably, levonorgestrel. The system is an improvement of the prior art because it has an improved delivery rate of levonorgestrel, which is typically impermeable to the skin. The improved delivery rate allows for a reduced skin permeation time of the active agents allowing high blood levels of the hormones to provide sufficient and adequate contraception. A reduced size of the transdermal patch can be utilized because of the improved delivery rate of levonorgestrel.
Typically, combinations of synthetic estrogen and synthetic progestin have been used in the past in orally administered dosage forms to control fertility. If a natural estrogen (17 beta estradiol) and progestin (progesterone) combination is to be used in the oral contraceptive pills, very large doses of these two hormones will be needed because of very extensive hepatic first-pass metabolism of the two hormones in the liver. The resulting metabolic products often cause undesired side effects. Therefore, a combination of synthetic progestin and estrogen are used to overcome the deficiencies.
Although the combination of synthetic progestin and estrogen is very effective in suppressing ovulation, certain undesirable side effects are still prevalent with this type of oral contraceptive. The incidence of thromboembolic and related vascular disorders, including stroke and myocardial infarction, is higher in women using oral contraceptives; the relative risk may be eleven times greater in users as compared to a control population. Further, the risk increases sharply in women over 35 years of age. Contraceptive use has also been associated with increased evidence of benign liver tumors and an increased risk of gallbladder disease. Additionally, fetal abnormalities may result if the mother continues to take the pill after becoming pregnant. Finally, some possible, but unproven complications of contraceptive use include breast cancer, and cancer of the uterus, cervix and vagina.
An ideal and patient-acceptable fertility control system should provide the following advantages: minimized side effects, increased ease of administration, rapid termination of treatment, and improved patient compliance. In recent years, considerable attention has been directed to the development of implantable, intrauterine, cervical or vaginal fertility control delivery systems to provide a prolonged and controlled administration of steroidal hormones to the body for achieving fertility control. However, none of the delivery systems developed so far can be considered ideal and free of side effects.
On the other hand, absorption of pharmaceuticals through the skin, i.e., transdermal drug delivery provides avoidance of many undesirable side effects. Specifically, transdermal rate-controlled drug administration provides: (i) avoidance of the risk and inconvenience of intravenous therapy and of the variability in absorption and metabolism associated with oral therapy; (ii) continuity of drug administration, permitting the use of a pharmacologically active agent with short biological half-life; (iii) efficacy can be achieved with lower total daily dosage of drug, since there is reduced degradation in the digestive system; (iv) less chance of over- or under-dosing; (v) provision of a simplified medication regimen; and (vi) ability to rapidly terminate the drug infusion, if needed, by removal of the drug delivery system from the skin surface.
It is, therefore, highly desired that transdermal systems be provided which permit 1) use of either synthetic or natural estrogen, 2) use of high levels of progestin, 3) use of a minimum number of dosage units for each menstrual cycle, and 4) that provide sufficiently high levels of estrogen and progestin hormones to provide high assurance of fertility control without a high amount of undesired metabolic or chemical degradative products.
In recent years various transdermal contraceptive delivery systems for fertility control in females have been developed.
U.S. Pat. No. 5,567,922 discloses the delivery of a natural estrogen, 17-beta estradiol, or ethinyl estradiol or a combination thereof with an amount of natural progestrogen or a progestin in a dosage unit comprising a backing layer and an adjoining polyacrylate adhesive polymer layer which releases the hormones.
U.S. Pat. No. 5,296,230 describes a transdermal fertility controlling polymer matrix dosage unit comprising a backing layer and a polymer matrix disc layer which is adhered to the backing layer comprising microdispersed dosage amounts of estrogen and progestin hormones, the polymer matrix disc layer having a surface of about 20 cm2.
U.S. Pat. No. 5,788,983 discloses a transdermal polymer dosage unit, a backing layer and a reservoir layer, the reservoir layer having multiple regions which contact the skin during use and optionally contain different pharmaceutical therapeutic agents providing a variable rate of absorption.
U.S. Pat. No. 5,762,956 describes a transdermal contraceptive delivery device and a method of fertility control utilizing the device. The system comprises a backing layer, and an adhesive polymer matrix, which has dispersed therein hormones effective for controlling fertility, as well as a combination of skin permeation enchancers. The adhesive polymer matrix provides a site for where the hormones and skin permeation enhancers are dispersed but also serves to adhere the delivery system in intimate contact with the skin of the subject being treated to permit the hormones to be absorbed transdermally. Typically about 300 to 400 pg/ml of levonorgestrel are released into the blood stream within a suitable period of time. It has been found that this level of levonorgestrel released into the bloodstream by transdermal route for the indicated period of time may be insufficient for effective and safe fertility control.
The present invention is an improvement over the deficiencies of the prior art in that it provides high serum levels of levonorgestrel and a desired profile of levonorgestrel for contraception and a desired level and profile of ethinyl estradiol while maintaining minimal side effects.